Substituted 3-phenyl-5-alkoxy-1,3,4-oxadiazol-2-ones, their preparation and their use as pharmaceuticals

ABSTRACT

Substituted 3-phenyl-5-alkoxy-1,3,4-oxadiazol-2-ones of the formula 1 are described,  
                 
 
     in which R 1  is substituted C 1 -C 6 -alkyl and C 3 -C 9 -cycloalkyl, R 2 , R 3 , R 4  and R 5  are hydrogen, halogen, nitro, C 1 -C 4 -alkyl, C 1 -C 9 -alkyloxy, substituted C 6 -C 10 -aryl-C 1 -C 4 -alkyloxy, C 6 -C 10 -aryloxy, C 6 -C 10 -aryl, C 3 -C 8 -cycloalkyl or O—C 3 —C 8 -cycloalkyl, or 2-oxopyrrolidin-1-yl, 2,5-dimethylpyrrol-1-yl or NR 6 -A-R 7 , with the proviso that R 2 , R 3 , R 4  and R 5  are not simultaneously hydrogen, and at least one of the radicals R 2 , R 3 , R 4  or R 5  is the radical 2-oxopyrrolidin-1-yl, 2,5-dimethylpyrrol-1-yl or NR 6 -A-R 7 , wherein R 6 =hydrogen, C 1 -C 4 -alkyl or substituted C 6 -C 10 -aryl-C 1 -C 4 -alkyl, A=a single bond, CO n , SO n  or CONH, n=1 or 2, R 7 =hydrogen, substituted C 1 -C 18 -alkyl, C 2 -C 18 -alkenyl, C 6 -C 10 -aryl-C 1 -C 4 -alkyl, C 5 -C 8 -cycloalkyl-C 1 -C 4 -alkyl, C 5 -C 8 -cycloalkyl, C 6 -C 10 -aryl-C 2 -C 6 -alkenyl, C 6 -C 10 -aryl, biphenylyl, biphenylyl-C 1 -C 4 -alkyl, indanyl, or the group Het-(CH 2 ) r —, wherein r=0, 1, 2 or 3 and Het=a saturated or unsaturated 5-7-membered heterocycle, which may be optionally benzo-fused and optionally substituted, and proceses for their preparation. The compounds of formula 1 show an inhibitory effect on hormone-sensitive lipase, HSL.

[0001] This invention relates to substituted3-phenyl-5-alkoxy-1,3,4-oxadiazol-2-ones, which show an inhibitoryeffect on hormone-sensitive lipase (HSL), and their pharmaceuticallyacceptable salts or acid addition salts. The present invention furtherrelates to processes for the preparation of3-phenyl-5-alkoxy-1,3,4-oxadiazol-2-ones, to the use of3-phenyl-5-alkoxy-1,3,4-oxadiazol-2-ones and their pharmaceuticallyacceptable salts or acid addition salts as pharmaceuticals, includingtheir use as inhibitors of HSL, and to pharmaceutical compositionscomprising 3-phenyl-5-alkoxy-1,3,4-oxadiazol-2-ones and theirpharmaceutically acceptable salts or acid addition salts, includingtheir use in the treatment of non-insulin dependent diabetes mellitusand diabetic syndrome.

[0002] Certain 5-alkoxy-1,3,4-oxadiazol-2-ones substituted with anortho-substituted phenyl ring or with fused-on five- or six-memberedrings have anthelmintic (DE-A 26 04 110) and insecticidal effects (DE-A26 03 877, EP-B 0 048 040, EP-B 0 067 471).

[0003] Certain 5-phenoxy-1,3,4-oxadiazol-2-ones with anortho-substituted phenyl ring as substituents show an endoparasiticidaleffect (EP-A 0 419 918).

[0004] An aim of the invention was to find compounds which show aninhibitory effect on hormone-sensitive lipase, HSL.

[0005] The present invention relates to substituted3-phenyl-5-alkoxy-1,3,4-oxadiazol-2-ones of the formula 1:

[0006] in which:

[0007] R¹ is C₁-C₆-alkyl, C₃-C₉-cycloalkyl, wherein both groups areoptionally substituted one or more times by phenyl, C₁-C₄-alkyloxy,S—C₁—C₄-alkyl, N(C₁-C₄-alkyl)₂, and wherein phenyl is optionallysubstituted one or more times by halogen, C₁-C₄-alkyl, C₁-C₄-alkyloxy,nitro, CF₃; and

[0008] R², R³, R⁴ and R⁵ independently of one another are hydrogen,halogen, nitro, C₁-C₄-alkyl, C₁-C₉-alkyloxy; C₆-C₁₀-aryl-C₁-C₄-alkyloxy,C₆-C₁₀-aryloxy, C₆-C₁₀-aryl, C₃-C₈-cycloalkyl or O—C₃-C₈-cycloalkyl,each of which is optionally substituted once, twice or three times byhalogen, CF₃, C₁-C₄-alkyloxy or C₁-C₄-alkyl; 2-oxopyrrolidin-1-yl,2,5-dimethylpyrrol-1-yl or NR⁶-A-R⁷, with the proviso that R², R³, R⁴and R⁵ are not simultaneously hydrogen, and at least one of the radicalsR², R³, R⁴ or R⁵ is the radical 2-oxopyrrolidin-1-yl,2,5-dimethylpyrrol-1-yl, or NR⁶-A-R⁷, and wherein:

[0009] R⁶ is hydrogen, C₁-C₄-alkyl or C₆-C₁₀-aryl-C₁-C₄-alkyl, whereinaryl may be substituted by halogen, CF₃, C₁-C₈-alkyloxy or C₁-C₄-alkyl;

[0010] A is a single bond, CO_(n), SO_(n), or CONH;

[0011] n is 1 or 2;

[0012] R⁷ is hydrogen, C₁-C₁₈-alkyl or C₂-C₁₈-alkenyl, whereinC₁-C₁₈-alkyl or C₂-C₁₈alkenyl are optionally substituted one to threetimes by C₁-C₄-alkyl, halogen, CF₃, C₁-C₄-alkyloxy, N(C₁-C₄-alkyl)₂,—COOH, C₁-C₄-alkyloxycarbonyl, C₆-C₁₂-aryl, C₆-C₁₂-aryloxy,C₆-C₁₂-arylcarbonyl, C₆-C₁₀-aryl-C₁-C₄-alkyloxy or oxo, wherein aryl isin turn optionally substituted by halogen, C₁-C₄-alkyl, aminosulfonyl ormethylmercapto;

[0013] C₆-C₁₀-aryl-C₁-C₄-alkyl, C₅-C₈-cycloalkyl-C₁-C₄-alkyl,C₅-C₈-cycloalkyl, C₆-C₁₀-aryl-C₂-C₆-alkenyl, C₆-C₁₀-aryl, biphenylyl,biphenylyl-C₁-C₄-alkyl, indanyl, each of which is optionally substitutedonce or twice by C₁-C₁₈-alkyl, C₁-C₁ ₈-alkyloxy, C₃-C₈-cycloalkyl, COOH,hydroxyl, C₁-C₄-alkylcarbonyl, C₆-C₁₀-aryl-C₁-C₄-alkyl,C₆-C₁₀-aryl-C₁-C₄-alkyloxy, C₆-C₁₀-aryloxy, nitro, cyano, C₆-C₁₀-aryl,fluorosulfonyl, C₁-C₆-alkyloxycarbonyl, C₆-C₁₀-arylsulfonyloxy, pyridyl,NHSO₂-C₆-C₁₀-aryl, halogen, CF₃ or OCF₃, wherein alkyl is in turnoptionally substituted by C₁-C₄-alkyloxycarbonyl, CF₃ or carboxyl, andaryl is also optionally substituted by halogen, CF₃ or C₁-C₄-alkyloxy;

[0014] or the group Het-(CH₂)_(r)—,

[0015] wherein r=0, 1, 2 or 3 and Het=a saturated or unsaturated5-7-membered heterocycle, optionally benzo-fused and optionallysubstituted by C₁-C₄-alkyl, C₆-C₁₀-aryl, halogen, C₁-C₄-alkyloxy,C₁-C₄-alkyloxycarbonyl, C₆-C₁₀-aryl-C₁-C₄-alkyl,C₆-C₁₀-aryl-C₁-C₄-alkylmercapto or nitro, wherein the benzo-fused arylis in turn optionally substituted by halogen, C₁-C₄-alkyloxy or CF₃ andthe alkyl in arylalkyl is also optionally by methoxy and CF₃,

[0016] and their pharmaceutically acceptable salts and acid additionsalts.

[0017] Said aryl radicals are optionally substituted one or more timesby C₁-C₉-alkyl, C₁-C₈-alkyloxy, halogen, and trifluoromethyl. Saidcycloalkyl radicals are optionally substituted one or more times byC₁-C₄-alkyl, C₆-C₁₀-aryl, and said alkyl radicals are optionallysubstituted by hydroxyl, di-C₁-C₄-alkylamino and fluorine. Halogen isfluorine, chlorine, bromine, generally fluorine and chlorine. Alkyl,alkenyl, alkyloxy, etc. are branched or unbranched. The phrase “isoptionally substituted” means that the relevant group is or is notsubstituted.

[0018] Pharmaceutically acceptable salts of compounds of the formula 1include their organic and inorganic salts, as described in Remington'sPharmaceutical Sciences (A. R. Gennard Editor, Mack Publishing Co.,Easton, Pa., USA, 17^(th) Ed., p 1418, (1985)). Examples of acidicgroups include, inter alia, sodium, potassium, calcium and ammoniumsalts. Examples of basic groups include, inter alia, salts ofhydrochloric acid, sulfuric acid, phosphoric acid, or of carboxylicacids or sulfonic acids, such as, for example, acetic acid, citric acid,benzoic acid, maleic acid, fumaric acid, tartaric acid andp-toluenesulfonic acid.

[0019] Typical compounds of the formula 1 are those in which:

[0020] R¹ is C₁-C₄-alkyl; and/or

[0021] R⁵ is hydrogen; and/or

[0022] R² is hydrogen, halogen, C₁-C₄-alkyl, C₁-C₉-alkyloxy or amino.

[0023] Further examples of compounds of the formula 1 are those inwhich:

[0024] R³ is hydrogen, C₁-C₄-alkyl, C₆-C₁₀-aryl-C₁-C₄-alkyloxy, which isoptionally substituted in the aryl moiety by halogen, or is NR⁶-A-R⁷wherein

[0025] R⁶=hydrogen or benzyl,

[0026] A=single bond and

[0027] R⁷=C₆-C₁₀-aryl-C₁-C₄-alkyl, which is optionally substituted byhalogen, CF₃, cyano, phenyl-C₁-C₄-alkyloxy, CF₃-phenoxy,C₅-C₈-cycloalkyl or fluorosulfonyloxy;

[0028] C₁-C₁₂-alkyl, which is optionally substituted by C₁-C₄-alkyloxy,phenyl, CF₃ or phenyl-C₁-C₄-alkyloxy; C₂-C₁₂-alkenyl;

[0029] or the group Het-(CH₂)_(r)—,

[0030] wherein r=0 or 1, and Het=a saturated or unsaturated 5-7-memberedheterocycle, which is optionally benzo-fused and optionally substitutedby C₁-C₄-alkyl or halogen.

[0031] Additional compounds of the formula 1 are those in which:

[0032] R⁴ is hydrogen, 2-oxopyrrolidin-1-yl, 2,5-dimethylpyrrol-1-yl orC₆-C₁₀-aryl-C₁-C₄-alkyloxy, which is optionally substituted by halogen,and/or: compounds of the formula 1 in which: R⁴ is NR⁶-A-R⁷, wherein

[0033] R⁶=hydrogen or methyl,

[0034] A=single bond and

[0035] R⁷=hydrogen;

[0036] C₁-C₁₂-alky, which is optionally substituted once or twice byhalogen;

[0037] C₂-C₁₈-alkenyl, which is optionally substituted once or twice byC₁-C₄-alkyl or C₁-C₄-alkyloxycarbonyl;

[0038] C₆-C₁₀-aryl-C₁-C₄-alky, which is optionally substituted byhalogen, C₁-C₆-alkyloxy, CF₃, cyano, C₅-C₆-cycloalkyl,C₁-C₄-alkyloxycarbonyl, C₆-C₁₀-aryl-C₁-C₄-alkyl,C₆-C₁₀-aryl-C₁-C₄-alkyloxy, wherein aryl is further optionallysubstituted by halogen or CF₃;

[0039] C₅-C₈-cycloalkyl-C₁-C₄-alkyl;

[0040] or the group Het-(CH₂)_(r)—,

[0041] wherein r=1, 2 or 3 and Het=a saturated or unsaturated5-7-membered heterocycle, which is optionally substituted by halogen,C₁-C₄-alkyloxy or C₁-C₄-alkyloxycarbonyl, and/or compounds of theformula 1 in which:

[0042] R⁴ is NR⁶-A-R⁷, wherein

[0043] R⁶=hydrogen,

[0044] A=—CO— and

[0045] R⁷=C₁-C₁₈-alkyl, which is optionally substituted by halogen,phenyl, phenoxy, phenylcarbonyl or C₁-C₄-alkyloxycarbonyl, whereinphenoxy is optionally substituted by methyl, halogen or methylmercapto;

[0046] C₂-C₁₈-alkenyl, which is optionally substituted by C₆-C₁₀-aryl;

[0047] C₆-C₁₀-aryl, which is optionally substituted by halogen,C₁-C₈-alkyl, phenyl-C₁-C₄-alkyl, CF₃, OCF₃, fluorosulfonyl,C₁-C₄-alkyloxycarbonyl, phenoxy, wherein aryl is optionally substitutedby C₁-C₄-alkyloxy;

[0048] C₆-C₁₀-aryl-C₁-C₄-alkyl, wherein alkyl is optionally substitutedby methoxy or CF₃ and aryl by halogen;

[0049] or the group Het-(CH₂)_(r)—,

[0050] wherein r=0 and Het=a saturated or unsaturated 5-7-memberedheterocycle, which is optionally benzo-fused and optionally substitutedby C₁-C₄-alkyl, halogen, C₁-C₄-alkyloxy, halophenyl orhalobenzylmercapto, wherein benzo-fused aryl is optionally substitutedby halogen or methoxy, and/or compounds of the formula 1 in which:

[0051] R⁴ is NR⁶-A-R⁷, wherein

[0052] R⁶=hydrogen,

[0053] A=—CO₂— and

[0054] R⁷=C₁-C₁₈-alkyl, which is substituted by CF₃ or phenyl;

[0055] C₆-C₁₀-aryl;

[0056] C₆-C₁₀-aryl-C₁-C₄-alkyl, which is substituted by C₁-C₄-alkyl,halogen, CF₃ or OCF₃, benzyloxy or phenyl;

[0057] or the group Het-(CH₂)_(r)—,

[0058] wherein r=0 or 1 and Het=a saturated or unsaturated 5-7-memberedheterocycle, which is optionally benzo-fused and optionally substitutedby C₁-C₄-alkyl or benzyl, and/or compounds of the formula 1 in which:

[0059] R⁴ is NR⁶-A-R⁷, wherein

[0060] R⁶=hydrogen,

[0061] A=—SO₂— and

[0062] R⁷=C₁-C₆-alky, which is optionally substituted by CF₃;

[0063] C₂-C₄-alkenyl, which is optionally substituted by phenyl;

[0064] C₆-C₁₀-aryl, which is optionally substituted by C₁-C₆-alkyl,halogen,

[0065] C₁-C₄-alkyloxy or benzyl;

[0066] biphenylyl-C₁-C₄-alkyl substituted by halogen;

[0067] or the group Het-(CH₂)_(r)—,

[0068] wherein r=0 and Het=a saturated or unsaturated 5-7-memberedheterocycle, and/or compounds of the formula 1 in which:

[0069] R⁴ is NR⁶-A-R⁷, wherein

[0070] R⁶=hydrogen,

[0071] A=—CO—NH— and

[0072] R⁷=C₁-C₁₀-alkyl, which is optionally substituted byC₁-C₄-alkyloxycarbonyl, N(C₁-C₄-alkyl)₂ or phenyl, which is in turnoptionally substituted by halogen or aminosulfonyl;

[0073] C₆-C₁₀-aryl, which is optionally substituted by C₁-C₆-alkyl,C₁-C₆-alkyloxy, C₁-C₆-alkyloxycarbonyl, phenoxy, OCF₃, benzyl orpyridyl, wherein alkyl is optionally substituted byC₁-C₄-alkyloxycarbonyl or carboxyl;

[0074] C₅-C₈-cycloalky, which is optionally substituted by hydroxyl, orindanyl;

[0075] or the group Het-(CH2)^(r)—,

[0076] wherein r=0 or 1 and Het=a saturated or unsaturated 5-7-memberedheterocycle, which is optionally substituted by benzyl.

[0077] Other typical compounds of the formula 1 are those in which R¹ ismethyl.

[0078] Representative compounds of the formula 1 are those mentioned inExamples 21, 22, 27, 28, 30 to 34, 36 to 42, 53, 54, 58, 60, 62, 65, 69,71, 74, 92, 97,107,116,128, 130, 136,139,142,152,166 and 171.

[0079] The compounds of the invention have a surprising inhibitoryeffect on hormone-sensitive lipase, HSL, an allosteric enzyme inadipocytes, which is inhibited by insulin and is responsible for thebreakdown of fats in fat cells and for the transfer of fat constituentsinto the blood stream. Inhibition of this enzyme thus corresponds to aninsulin-like effect of the compounds of the invention, which eventuallyleads to a reduction of free fatty acids in the blood and of bloodglucose. Therefore, the compounds of the invention can be employed inthe treatment of metabolic disturbances such as, for example,non-insulin-dependent diabetes mellitus, diabetic syndrome, and directdamage to the pancreas.

[0080] The compounds of the invention can be prepared in various ways bymethods known per se.

[0081] For example, substituted 3-phenyl-5-alkoxy-1,3,4-oxadiazol-2-onesof the formula 1 can be prepared by reacting hydrazines of the formula 2with chloroformic esters of the formula 3 or other reactive carbonicester derivatives, in which R¹, R², R³, R⁴ and R⁵ are as defined above,to give the compounds of the formula 4, which are acylated withphosgene, carbonyldiimidazole, diphosgene or triphosgene, cyclized andconverted, where appropriate, by further chemical modification of theradicals R²-R⁵, such as, for example, by reduction of nitro to aminoradicals by known processes, and subsequent acylation or alkylation,into compounds of the formula 1. Since acids are usually liberated inthese reactions, neutralization is advisable by adding bases such aspyridine, triethylamine, sodium hydroxide solution or alkali metalcarbonates. The reactions can be carried out in wide temperature ranges.It has proved advantageous to operate in the temperature range from 0°C. to the boiling point of the solvent used. Examples of solventsemployed are methylene chloride, THF, DMF, toluene, ethyl acetate,n-heptane, dioxane, and diethyl ether.

[0082] The hydrazines of the formula 2 can be prepared by known methods,for example by diazotization of the corresponding anilines and

[0083] subsequent reduction by known methods or by nucleophilicsubstitution of suitably substituted phenyl derivatives of the formula 6(X=F, Cl, Br, l, OSO₂CF₃) with hydrazine hydrate. Such suitable phenylderivatives may be nitro-substituted halobenzenes, such as fluoro- andchloronitrobenzenes, from which the compounds of the invention can beprepared by known methods at a suitable point in the synthetic route byreduction and reaction with acylating or alkylating agents such as, forexample, acid chlorides, anhydrides, isocyanates, chloroformic esters,sulfonyl chlorides or alkyl and arylalkyl halides, or by reductivealkylation with aldehydes.

[0084] The effect of the compounds of the invention on HSL was testedusing the following enzyme assay system:

[0085] Enzyme Preparation:

[0086] Preparation of Partially Purified HSL:

[0087] Isolated rat fat cells were obtained from epididymal adiposetissue from untreated male rats (Wistar, 220-250 g) by collagenasetreatment according to published methods (e.g., S. Nilsson et al., Anal.Biochem. 158:399-407 (1986); G. Fredrikson et al., J. Biol. Chem.256:6311-6320 (1981); H. Tornquist et al., J. Biol. Chem. 251:813-819(1976)). The fat cells from 10 rats were washed three times by flotationwith 50 ml each time of homogenization buffer (25 ml tris/HCl, pH 7.4,0.25 M sucrose, 1 mM EDTA, 1 mM DTT, 10 μg/ml leupeptin, 10 μg/mlantipain, 20 μg/ml pepstatin) and finally taken up in 10 ml ofhomogenization buffer. The fat cells were homogenized in aTeflon-in-glass homogenizer (Braun-Melsungen) by 10 strokes at 1500 rpmand 15° C. The homogenate was centrifuged (Sorvall SM24 tubes, 5000 rpm,10 min, 4° C.). The subnatant between the fatty layer at the top and thepellet was removed and the centrifugation was repeated. The subnatantresulting therefrom was recentrifuged (Sorvall SM24 tubes, 20000 rpm, 45min, 4° C.). The subnatant was removed and mixed with 1 g ofheparin-Sepharose (Pharmacia-Biotech, CL-6B, 5×washed with 25 mMtris/HCl, pH 7.4,150 mM NaCl). After the mixture had been incubated at4° C. for 60 min (shaking at 15-min intervals), it was centrifuged(Sorvall SM24 tubes, 3000 rpm, 10 min, 4° C.). The supernatant wasadjusted to pH 5.2 by adding glacial acetic acid and incubated at 4° C.for 30 min. The precipitates were collected by centrifugation (SorvallSS34, 12000 rpm, 10 min, 4° C.) and suspended in 2.5 ml of 20 mMtris/HCl, pH 7.0,1 mM EDTA, 65 mM NaCl, 13% sucrose, 1 mM DTT, 10 μg/mlleupeptin/pepstatin/antipain. The suspension was dialyzed against 25 mMtris/HCl, pH 7.4, 50% glycerol, 1 mM DTT, 10 μg/ml leupeptin, pepstatin,antipain at 4° C. overnight and then loaded onto a hydroxy apatitecolumn (0.1 g per 1 ml of suspension, equilibrated with 10 mM potassiumphosphate, pH 7.0, 30% glycerol, 1 mM DTT). The column was washed withfour volumes of equilibration buffer at a flow rate of 20 to 30 ml/h.The HSL was eluted with one volume of equilibration buffer containing0.5 M potassium phosphate, and then dialyzed (see above) andconcentrated 5- to 10-fold by ultrafiltration (Amicon Diaflo PM 10filter) at 4° C. The partially purified HSL can be stored at −70° C. for4 to 6 weeks.

[0088] Assay:

[0089] To prepare the substrate, 25-50 μCi of [³H]trioleoylglycerol (intoluene), 6.8 μmol of unlabeled trioleoylglycerol and 0.6 mg ofphospholipids (phosphatidylcholine/phosphatidylinositol 3:1 w/v) weremixed, dried with N₂ and then taken up in 2 ml of 0.1 M KP_(i) (pH 7.0)by ultrasonic treatment (Branson 250, microtip, setting 1-2, 2×1 min at1-min intervals). After addition of 1 ml of KP_(i) and renewedultrasonic treatment (4×30 sec on ice in 30-sec intervals), 1 ml of 20%BSA (in KP_(i)) was added (final concentration of trioleoylglycerol 1.7mM). For the reaction, 100 μl of substrate solution were pipetted into100 82 l of HSL solution (HSL prepared as above, diluted in 20 mMKP_(i), pH 7.0, 1 mM EDTA, 1 mM DTT, 0.02% BSA, 20 μg/ml pepstatin, 10μg/ml leupeptin) and incubated at 37° C. for 30 min. Addition of 3.25 mlof methanol/chloroform/heptane (10:9:7) and of 1.05 ml of 0.1 M K₂CO₃,0.1 M boric acid (pH 10.5) was followed by thorough mixing and finallycentrifugation (800×g, 20 min). After phase separation, one equivalentof the upper phase (1 ml) was removed and the radioactivity wasdetermined by liquid scintillation measurement.

[0090] Evaluation:

[0091] Substances were normally tested in four independent mixtures. Theinhibition of the HSL enzymatic activity by a test substance wasdetermined by comparison with an uninhibited control reaction. The IC₅₀was calculated via an inhibition plot with at least 10 concentrations ofthe test substance. The data was analyzed using the software packageGRAPHIT, Elsevier-BIOSOFT.

[0092] Selected compounds of the invention showed the following effect,as measured by this assay: Compound of Example No. IC₅₀ (μM) 21 10 22 127 10 28 6 30 1 31 10 32 3 33 0.2 34 1 36 10 37 1 38 1 39 1 40 10 41 0.142 1 53 1 54 1 58 0.8 60 0.2 62 0.3 65 1 69 0.03 71 0.02 74 0.04 92 0.2597 0.03 107  0.12 116  0.1 128  0.6 130  0.5 136  0.5 139  0.4 142  0.2152  0.2 166  0.2 171  0.6

[0093] The following examples illustrate the preparation methods indetail without restricting them.

EXAMPLE 1

[0094] 3-Methyl-4-nitrophenylhydrazine

[0095] 5 g of hydrazine hydrate were slowly added dropwise to a solutionof 15.9 g of 2-methyl-4-fluoronitrobenzene in 10 ml ofN-methylpyrrolidone at room temperature, and the mixture was heated withstirring at 65° C. for 4 hours. The product was precipitated by adding70 ml of water and was filtered off with suction and then recrystallizedfrom isopropanol.

[0096] Yield:13.3 g m.p.: 138° C.

[0097] The following examples were prepared in an analogous way: CLEXAMPLE 2

[0098] 3-Fluoro-4-nitrophenylhydrazine

[0099] M.p.: 130° C.

EXAMPLE 3

[0100] 2-Chloro-4-nitrophenylhydrazine

[0101] M.p.:144° C.

EXAMPLE 4

[0102] 2-Methyl-4-nitrophenylhydrazine

[0103] M.p.:135° C.

EXAMPLE 5

[0104] 3-(4-Fluorobenzyloxy)-2-nitrophenylhydrazine

[0105] M.p.:164° C.

[0106] The starting compound 2-fluoro-4-(4-fluorobenzyloxy)nitrobenzene(m.p.: 99° C.) was prepared by alkylation of 3-fluoro-4-nitrophenol with4-fluorobenzyl chloride in DMF in the presence of potassium carbonate.

EXAMPLE 6

[0107] 3-(4-Fluorobenzyloxy)-4-nitrophenylhydrazine (intermediate)

[0108] M.p.: 145° C.

EXAMPLE 7

[0109] 4-(4-Chlorophenoxy)-3-nitroaniline

[0110] 1.4 g of potassium carbonate were added to a solution of 1.29 gof 4-chlorophenol in 8 ml of DMF and, after stirring for 30 minutes, 1.6g of 4-fluoro-3-nitroaniline were added, and the mixture was stirred at100° C. for 3 hours. After cooling, 80 ml of water were added and, afterbrief stirring, the precipitate was filtered off with suction and driedin vacuo at 40° C.

[0111] Yield: 2.0 g; m.p.: 101° C.

EXAMPLE 8

[0112] 4-(4-Chlorophenoxy)-3-nitrophenylhydrazine

[0113] A solution of 0.52 g of sodium nitrite in 5 ml of water was addeddropwise to a stirred mixture consisting of 1.9 g of4-(4-chlorophenoxy)-3-nitroaniline, 25 ml of concentrated hydrochloricacid and 25 ml of ethanol cooled to 0° C., and the mixture was thenstirred at 0° C. for 60 min and subsequently added dropwise to asuspension of 8.5 g of tin dichloride dihydrate in 8 ml of concentratedHCl. The precipitate was filtered off with suction, washed with water,suspended in 200 ml of water under nitrogen and decomposed with 100 mlof 30% strength sodium hydroxide solution at 10-15° C. The oil formedwas extracted by shaking with ethyl acetate and washed with water, andthe organic phase was dried with sodium sulfate. The product was thenprecipitated with isopropanolic HCl, filtered off with suction and driedin vacuo.

[0114] Yield: 1.1 g; m.p.: 221° C.

EXAMPLE 9

[0115] Methyl N′-(4-nitro-2-methylphenyl)hydrazinoformate

[0116] 0.43 ml of methyl chloroformate was cautiously added dropwise toa mixture consisting of 0.84 g of 2-methyl-4-nitrophenylhydrazine, 15 mlof NMP and 2 ml of pyridine while cooling in ice, and the mixture wasthen stirred for 2 hours while slowly warming to RT. After dilution with50 ml of water, the mixture was stirred over night and the solid wasdried in vacuo at 40° C.

[0117] Yield: 0.81 g; m.p.:153° C.

[0118] The following examples were prepared in an analogous way:

EXAMPLE 10

[0119] Methyl N′-(4-nitrophenyl)hydrazinoformate (intermediate)

[0120] M.p.: 179° C.

EXAMPLE 11

[0121] Methyl N′-(3-fluoro-4-nitrophenyl)hydrazinoformate

[0122] M.p.: 127.4° C.

EXAMPLE 12

[0123] Methyl N′-(3-methyl-4-nitrophenyl)hydrazinoformate

[0124] M.p.: 159° C.

EXAMPLE 13

[0125] Methyl N′-(2-chloro-4-nitrophenyl)hydrazinoformate

[0126] M.p.: 156° C.

EXAMPLE 14

[0127] Methyl N′-(3-(4-fluorobenzyloxy)-4-nitrophenyl)hydrazinoformate(intermediate)

[0128] M.p.: 166° C.

EXAMPLE 15

[0129] Methyl N′-(3-(4-fluorobenzyloxy)-2-nitrophenyl)hydrazinoformate

[0130] M.p.: 193° C.

EXAMPLE 16

[0131] Methyl N′-(4-(4-chlorophenoxy)-3-nitrophenyl)hydrazinoformate

[0132] M.p.: 147° C.

EXAMPLE 17

[0133] Methyl N′-(3-piperidino-4-nitrophenyl)hydrazinoformate (-)

[0134] M.p.: 131° C.

[0135] The latter compound and the compound of Example 18 were preparedby reacting methyl N′-(3-fluoro-4-nitrophenyl)hydrazinoformate withpiperidine and N-benzyl-piperazine, respectively, in NMP at 80° C.

EXAMPLE 18

[0136] Methyl N′-(3-(N-benzylpiperazino)-4-nitrophenyl)hydrazinoformate

[0137] M.p.: 156° C.

EXAMPLE 19

[0138]5-Methoxy-3-(4-nitrophenyl)-3H-(1,3,4)oxadiazol-2-one

[0139] 2.5 g of methyl N′-(4-nitrophenyl)hydrazinoformate and 5 ml ofpyridine were taken up in 15 ml of methylene chloride and, whilestirring and cooling in ice, 3 ml of a 20% strength solution of phosgenein toluene were added dropwise. This mixture was left to stand at roomtemperature overnight and was diluted with a further 10 ml of methylenechloride and then washed 3 times with water. After drying over sodiumsulfate, the mixture was concentrated in vacuo, and the product waspurified by column chromatography (silica gel, solvents:methanol:methylene chloride=2:98) and recrystallized from isopropanol.

[0140] Yield:1.5 g m.p.: 151° C.

[0141] The following examples were prepared analogously to Example 4:

EXAMPLE 20

[0142] 5-Methoxy-3-(3-methyl-4-nitrophenyl)-3H-(1,3,4)oxadiazol-2-one

[0143] M.p.: 112° C.

EXAMPLE 21

[0144]5-Methoxy-3-(4-(4-chlorophenoxy-3-nitrophenyl)-3H-(1,3,4)oxadiazol-2-one

[0145] M.p.: oil

EXAMPLE 22

[0146]5-Methoxy-3-(3-(4-fluorobenzyloxy)-2-nitrophenyl)-3H-(1,3,4)oxadiazol-2-one

[0147] M.p.: 99° C.

EXAMPLE 23

[0148] 5-Methoxy-3-(2-methyl-4-nitrophenyl)-3H-(1,3,4)oxadiazol-2-one

[0149] M.p.: 111° C.

EXAMPLE 24

[0150]5-Methoxy-3-(3-(4-fluorobenzyloxy)-4-nitrophenyl)-3H-(1,3,4)oxadiazol-2-one

[0151] M.p.: 137° C.

EXAMPLE 25

[0152] 5-Methoxy-3-(4-aminophenyl)-3H-(1,3,4)oxadiazol-2-one

[0153] A mixture consisting of 1.4 g of5-methoxy-3-(4-nitrophenyl)-3H-(1,3,4)oxadiazol-2-one, 0.5 g of Pd/C and20ml of methanol was hydrogenated under atmospheric pressure at roomtemperature until the calculated amount of hydrogen had been taken up.The catalyst was then filtered off, and the solution was concentrated invacuo. The remaining semisolid residue was stirred with isopropanol andfiltered off with suction.

[0154] Yield: 0.75g; m.p.: 85° C.

EXAMPLE 26

[0155]5-Methoxy-3-(2-amino-4-(4-fluorobenzyloxy)phenyl)-3H-(1,3,4)oxadiazol-2-one

[0156] M.p.: oil

EXAMPLE 27

[0157]5-Methoxy-3-(3-amino-4-(4-chlorophenoxy)phenyl)-3H-(1,3,4)oxadiazol-2-one

[0158] M.p.: 133° C.

EXAMPLE 28

[0159] 5-Methoxy-3-(4-amino-3-methylphenyl)-3H-(1,3,4)oxadiazol-2-one

[0160] M.p.: 114° C.

EXAMPLE 29

[0161]5-Methoxy-3-(4-amino-3-(4-fluorobenzyloxy)phenyl)-3H-(1,3,4)oxadiazol-2-one

[0162] M.p.: 195° C.

EXAMPLE 30

[0163]5-Methoxy-3-(4-(4-chlorophenylacetylamino)phenyl)-3H-(1,3,4)oxadiazol-2-one

[0164] 201 mg of 4-chlorophenylacetyl chloride were added dropwise to amixture consisting of 200 mg of5-methoxy-3-(4-aminophenyl)-3H-(1,3,4)oxadiazol-2-one, 20 ml ofmethylene chloride and 0.1 ml of pyridine cooled in ice, and the mixturewas stirred at room temperature for 5 hours. Volatiles were removed invacuo. The residue was stirred with water and the solid was filtered offwith suction and dried at 40° C. in vacuo.

[0165] Yield: 318 mg; m.p.:161° C.

[0166] The following examples were prepared in an analogous way:

EXAMPLE 31:

[0167]5-Methoxy-3-(4-(4-chlorophenylacetylamino)-3-methylphenyl)-3H-(1,3,4)oxadiazol-2-one

[0168] M.p.: 190° C.

EXAMPLE 32

[0169]5-Methoxy-3-(4-octanoylamino-3-methylphenyl)-3H-(1,3,4)oxadiazol-2-one

[0170] M.p.: 110° C.

EXAMPLE 33

[0171]5-Methoxy-3-(4-(4-heptylbenzoylamino)phenyl)-3H-(1,3,4)oxadiazol-2-one

[0172] M.p.: 155° C.

EXAMPLE 34

[0173]5-Methoxy-3-(4-(4-butylphenylsulfonylamino)phenyl)-3H-(1,3,4)oxadiazol-2-one

[0174] M.p.: 135° C.

EXAMPLE 35

[0175]5-Methoxy-3-(4-(4-chlorobutanoylamino)-3-methylphenyl)-3H-(1,3,4)oxadiazol-2-one

[0176] M.p.: 137° C.

EXAMPLE 36

[0177]5-Methoxy-3-(4-pivaloylamino-3-methylphenyl)-3H-(1,3,4)oxadiazol-2-one

[0178] M.p.: 157° C.

EXAMPLE 3

[0179]5-Methoxy-3-(4-(4-chlorophenylsulfonylamino)-3-methylphenyl)-3H-(1,3,4)oxadiazol-2-one

[0180] M.p.: 147° C.

EXAMPLE 38

[0181]5-Methoxy-3-(4-(1-naphthylsulfonylamino)-3-methylphenyl)-3H-(1,3,4)oxadiazol-2-one

[0182] M.p.: 123° C.

EXAMPLE 39

[0183]5-Methoxy-3-(4-(2-phenylethenylsulfonylamino)-3-methylphenyl)-3H-(1,3,4)oxadiazol-2-one

[0184] M.p.: 129° C.

EXAMPLE 40

[0185]5-Methoxy-3-(4-(2,2,2-trifluoroethylsulfonylamino)-3-methylphenyl)-3H-(1,3,4)oxadiazol-2-one

[0186] M.p.: 151° C.

[0187] EXAMPLE 41

[0188]5-Methoxy-3-(4-(benzyloxycarbonylamino)-3-methylphenyl)-3H-(1,3,4)oxadiazol-2-one

[0189] M.p.: 115° C.

EXAMPLE 42

[0190]5-Methoxy-3-(4-(3,4-dichlorophenylaminocarbonylamino)-3-methylphenyl)-3H-(1,3,4)oxadiazol-2-one

[0191] M.p.: 210° C.

[0192] The latter compound was obtained by reacting5-methoxy-3-(4-amino-3-methylphenyl)-3H-(1,3,4)oxadiazol-2-one withequimolar amounts of 3,4-dichlorophenyl isocyanate in toluene at 50° C.

EXAMPLE 43

[0193]5-Methoxy-3-(4-(4-chlorophenylsulfonylamino)phenyl)-3H-(1,3,4)oxadiazol-2-one

[0194] M.p.: 169° C.

EXAMPLE 44

[0195]5-Methoxy-3-(4-(2-chlorophenylsulfonylamino)phenyl)-3H-(1,3,4)oxadiazol-2-one

[0196] M.p.: 171° C.

EXAMPLE 45

[0197]5-Methoxy-3-(4-(3-chlorophenylsulfonylamino)phenyl)-3H-(1,3,4)oxadiazol-2-one

[0198] M.p.: 141° C.

EXAMPLE 46

[0199]5-Methoxy-3-(4-(4-chlorophenylacetylamino)-3-(4-fluorobenzyloxy)phenyl)-3H-(1,3,4)oxadiazol-2-one

[0200] M.p.: 167° C.

EXAMPLE 47

[0201]5-Methoxy-3-(4-benzylsulfonylaminophenyl)-3H-(1,3,4)oxadiazol-2-one

[0202] M.p.: 153° C.

EXAMPLE 48

[0203]5-Methoxy-3-(4-(-2-(4′-chlorobiphenyl)ethyl)sulfonylamino)phenyl)-3H-(1,3,4)oxadiazol-2-one

[0204] M.p.: 165° C.

EXAMPLE 49

[0205]5-Methoxy-3-(4-isopropylsulfonylaminophenyl)-3H-(1,3,4)oxadiazol-2-one

[0206] M.p.: 190° C.

EXAMPLE 50

[0207] 5-Methoxy-3-(4-dimethylamino-3-methylphenyl)-3H-(1,3,4)oxadiazol-2-one

[0208] M.p.: 71° C.

[0209] The latter compound was obtained by reacting5-methoxy-3-(4-amino-3-methylphenyl)-3H-(1,3,4)oxadiazol-2-one withparaformaldehyde/formic acid in DMF at room temperature and was purifiedby column chromatography (silica gel, ethyl acetate:n-heptane=1:1).

EXAMPLE 51

[0210]5-Methoxy-3-(4-(4-chlorobenzylamino)-3-methylphenyl)-3H-(1,3,4)oxadiazol-2-one

[0211] M.p.: oil

[0212] The latter compound was obtained by reacting5-methoxy-3-(4-amino-3-methylphenyl)-3H-(1,3,4)oxadiazol-2-one with4-chlorobenzaldehyde/sodium borohydride in methanol/methylene chlorideat room temperature and was purified by column chromatography (silicagel, ethyl acetate:n-heptane=1:1).

EXAMPLE 52

[0213]5-Methoxy-3-(4-(2-oxopyrrolidin-1-yl)-3-methylphenyl)-3H-(1,3,4)oxadiazol-2-one

[0214] M.p.: oil

[0215] The latter compound was prepared by reacting5-methoxy-3-(4-(4-chlorobutanoylamino)-3-methylphenyl)-3H-(1,3,4)oxadiazol-2-onewith sodium hydride in dioxane at room temperature and purifying thecrude product by column chromatography (silica gel, methylenechloride:methanol=98:2).

EXAMPLE 53

[0216]5-Methoxy-3-(4-(4-oxopent-2-en-2-ylamino)-3-methylphenyl)-3H-(1,3,4)oxadiazol-2-one

[0217] M.p.: 143° C.

[0218] The latter compound was obtained by reacting5-methoxy-3-(4-amino-3-methylphenyl)-3H-(1,3,4)oxadiazol-2-one withequimolar amounts of acetylacetone in glacial acetic acid at 80° C. andwas isolated by precipitation by adding water and filtration.

EXAMPLE 54

[0219]5-Methoxy-3-(4-(2,5-dimethylpyrrol-1-yl)-3-methylphenyl)-3H-(1,3,4)oxadiazol-2-one

[0220] M.p.: oil

[0221] The latter compound was obtained by reacting5-methoxy-3-(4-amino-3-methylphenyl)-3H-(1,3,4)oxadiazol-2-one withequimolar amounts of acetonylacetone in glacial acetic acid at 80° C.Working up took place by dilution with water, extraction by shaking withethyl acetate and column chromatography (silica gel, methylene chloride)of the crude product obtained after concentration of the dried organicphase.

EXAMPLE 55

[0222]5-Methoxy-3-(3-(4-fluorobenzyloxy)-4-methylaminophenyl)-3H-(1,3,4)oxadiazol-2-one

[0223] M.p.: 98° C.

[0224] The latter compound was obtained as a by-product of thehydrogenation of 5-methoxy-3-(3-(4-fluorobenzyloxy)-4-nitrophenyl)-3H-(1,3,4)oxadiazol-2-one withplatinum dioxide as catalyst, in methanol, at room temperature underatmospheric pressure. Purification proceeded by column chromatography(silica gel, methylene chloride) after filtering off the catalyst andconcentrating the reaction mixture.

[0225] The compounds of Examples 56-199 were prepared analogously to theabove-mentioned examples.

EXAMPLE 56

[0226] 5-Methoxy-3-(3-aminophenyl)-3H-(1,3,4)oxadiazol-2-one

[0227] M.p.: 95° C.

EXAMPLE 57

[0228] 5-Methoxy-3-(3-dibenzylaminophenyl)-3H-(1,3,4)oxadiazol-2-one

[0229] M.p.: 71° C.

EXAMPLE 58

[0230] 5-Methoxy-3-(3-benzylaminophenyl)-3H-(1,3,4)oxadiazol-2-one

[0231] M.p.: oil

EXAMPLE 59

[0232]5-Methoxy-3-(4-(pyrid-2-yl)aminocarbonylaminophenyl)-3H-(1,3,4)oxadiazol-2-one

[0233] M.p.: 81° C.

EXAMPLE 60

[0234]5-Methoxy-3-(3-(4-fluorobenzyloxy)-4-benzyloxycarbonylaminophenyl)-3H-(1,3,4)oxadiazol-2-one

[0235] M.p.: oil

EXAMPLE 61

[0236] 5-Methoxy-3-(4-amino-2-methylphenyl)-3H-(1,3,4)oxadiazol-2-one

[0237] M.p.: oil

EXAMPLE 62

[0238]5-Methoxy-3-(3-methyl-4-(2-chlorobenzyloxycarbonylamino)phenyl)-3H-(1,3,4)oxadiazol-2-one

[0239] M.p.: 161° C.

EXAMPLE 63

[0240] 5-Methoxy-3-(4-amino-2-chlorophenyl)-3H-(1,3,4)oxadiazol-2-one

[0241] M.p.: 126° C.

EXAMPLE 64

[0242] 5-Methoxy-3-(2-chloro-4-nitrophenyl)-3H-(1,3,4)oxadiazol-2-one

[0243] M.p.: 92° C.

EXAMPLE 65

[0244]5-Methoxy-3-(2-methyl-4-benzyloxycarbonylaminophenyl)-3H-(1,3,4)oxadiazol-2-one

[0245] M.p.: 112° C.

EXAMPLE 66

[0246]5-Methoxy-3-(2-methyl-4-(4-trifluoromethoxybenzoylamino)phenyl)-3H-(1,3,4)oxadiazol-2-one

[0247] M.p.: 150° C.

EXAMPLE 67

[0248]5-Methoxy-3-(2-chloro-4-benzyloxycarbonylaminophenyl)-3H-(1,3,4)oxadiazol-2-one

[0249] M.p.: 150° C.

EXAMPLE 68

[0250] 5-Methoxy-3-(3-fluoro-4-nitrophenyl)-3H-(1,3,4)oxadiazol-2-one

[0251] M.p.: 127° C.

EXAMPLE 69

[0252]5-Methoxy-3-(4-(4-t-butylbenzoylamino)phenyl)-3H-(1,3,4)oxadiazol-2-one

[0253] M.p.: 173° C.

EXAMPLE 70

[0254]5-Methoxy-3-(4-(4-chlorobenzyloxycarbonylamino)phenyl)-3H-(1,3,4)oxadiazol-2-one

[0255] M.p.: 177° C.

EXAMPLE 71

[0256]5-Methoxy-3-(2-chloro-4-(4-heptylbenzoylamino)phenyl)-3H-(1,3,4)oxadiazol-2-one

[0257] M.p.: 135° C.

EXAMPLE 72

[0258]5-Methoxy-3-(4-(3,4-dichlorobenzoylamino)phenyl)-3H-(1,3,4)oxadiazol-2-one

[0259] M.p.: 200° C.

EXAMPLE 73

[0260]5-Methoxy-3-(4-(2-(4-chlorophenoxy)-2-methylpropionylamino)phenyl)-3H-(1,3,4)oxadiazol-2-one

[0261] M.p.: 153° C.

EXAMPLE 74

[0262]5-Ethoxy-3-(3-methyl-4-benzyloxycarbonylaminophenyl)-3H-(1,3,4)oxadiazol-2-one

[0263] M.p.: 94° C.

EXAMPLE 75

[0264]5-isopropoxy-3-(3-methyl-4-benzyloxycarbonylaminophenyl)-3H-(1,3,4)oxadiazol-2-one

[0265] M.p.: 119° C.

EXAMPLE 76

[0266]5-isopropoxy-3-(3-methyl-4-butyloxycarbonylaminophenyl)-3H-(1,3,4)oxadiazol-2-one

[0267] M. p.: 114° C.

EXAMPLE 77

[0268]5-isopropoxy-3-(3-methyl-4-(3-chlorophenylaminocarbonylamino)phenyl)-3H-(1,3,4)oxadiazol-2-one

[0269] M.p.: 201° C.

EXAMPLE 78

[0270]5-tert-Butoxy-3-(3-methyl-4-benzyloxycarbonylaminophenyl)-3H-(1,3,4)oxadiazol-2-one

[0271] M.p.: 113° C.

EXAMPLE 79

[0272]5-Methoxy-3-(3-methyl-4-phenoxycarbonylaminophenyl)-3H-(1,3,4)oxadiazol-2-one

[0273] M.p.: 145° C.

EXAMPLE 80

[0274]5-Methoxy-3-(3-methyl-4-(pyrid-3-ylcarbonylamino)phenyl)-3H-(1,3,4)oxadiazol-2-one

[0275] M.p.: oil

EXAMPLE 81

[0276]5-Methoxy-3-(3-methyl-4-(indan-2-ylaminocarbonylamino)phenyl)-3H-(1,3,4)oxadiazol-2-one

[0277] M.p.: 206° C.

EXAMPLE 82

[0278]5-Methoxy-3-(3-methyl-4-(pyrid-3-ylmethylaminocarbonylamino)phenyl)-3H-(1,3,4)oxadiazol-2-one

[0279] M.p.: 229° C.

EXAMPLE 83

[0280]5-Methoxy-3-(3-methyl-4-(pyrid-3-ylmethoxycarbonylamino)phenyl)-3H-(1,3,4)oxadiazol-2-one

[0281] M.p.: 232° C.

EXAMPLE 84

[0282]5-Methoxy-3-(3-fluoro-4-benzyloxycarbonylaminophenyl)-3H-(1,3,4)oxadiazol-2-one

[0283] M.p.: oil

EXAMPLE 85

[0284]5-Methoxy-3-(3-fluoro-4-(4-trifluoromethylbenzoylamino)phenyl)-3H-(1,3,4)oxadiazol-2-one

[0285] M.p.: oil

EXAMPLE 86

[0286]5-Methoxy-3-(3-benzyloxy-4-(4-trifluoromethylbenzoylamino)phenyl)-3H-(1,3,4)oxadiazol-2-one

[0287] M.p.: 159° C.

EXAMPLE 87

[0288]5-Methoxy-3-(3-fluoro-4-(4-tert-butylbenzoylamino)phenyl)-3H-(1,3,4)oxadiazol-2-one

[0289] M.p.: 144° C.

EXAMPLE 88

[0290]5-Methoxy-3-(3-methyl-4-(2,2,2-trifluoroethoxycarbonylamino)phenyl)-3H-(1,3,4)oxadiazol-2-one

[0291] M.p.: 141° C.

EXAMPLE 89

[0292]5-Methoxy-3-(3-methyl-4-piperidinocarbonylaminophenyl)-3H-(1,3,4)oxadiazol-2-one

[0293] M.p.: 154° C.

EXAMPLE 90

[0294]5-Methoxy-3-(4-(6-methoxybenzofuran-2-yl-carbonylamino)phenyl)-3H-(1,3,4)oxadiazol-2-one

[0295] M.p.: 191° C.

[0296] Further examples of the invention were prepared by the processesdescribed above and characterized by mass spectroscopy (M+1): ExampleMol. No. Chemical name: M + 1 wt.  91N-[4-(5-Methoxy-2-oxo-[1,3,4]oxadiazol-3- 362 361.4yl)phenyl]-3-methyl-benzenesulfonamide  923,4-Dimethoxy-N-[4-(5-methoxy-2-oxo-[1,3, 408 407.44]oxadiazol-3-yl)-phenyl]benzenesulfon- amide  93 Quinoline-8-sulfonicacid [4-(5-methoxy-2- 399 398.4 oxo-[1,3,4]oxadiazol-3-yl)phenyl]amide 94 N-[4-(5-Methoxy-2-oxo-[1,3,4]oxadiazol-3- 415 414.3yl)phenyl]-5-nitro-isophthalic acid mono- methyl ester  953-(2-Chlorophenyl)-5-methylisoxazole-4- 427 426.8 carboxylic acid[4-(5-methoxy-2-oxo-[1,3, 4]oxadiazol-3-yl)phenyl]amide  963,3,3-Trifluoro-2-methoxy-N-[4-(5-methoxy- 424 423.32-oxo-[1,3,4]oxadiazol-3-yl)phenyl]-2- phenylpropionamide  972-Fluoro-N-[4-(5-methoxy-2-oxo-[1,3,4] 330 329.3oxadiazol-3-yl)phenyl]-benzamide  98 Tetradecanoic acid[4-(5-methoxy-2-oxo-[1, 418 417.5 3,4]oxadiazol-3-yl)phenyl]amide  99N-[4-(5-Methoxy-2-oxo-[1,3,4]oxadiazol-3- 416 415.4yl)phenyl]-2-phenethyl-benzamide 100N-[4-(5-Methoxy-2-oxo-[1,3,4]oxadiazol-3- 479 478.4yl)phenyl]-2-(4-methoxyphenoxy)-5-nitro- benzamide 1012-(4-Benzyloxyphenyl)-N-[4-(5-methoxy-2- 432 431.4oxo-[1,3,4]oxadiazol-3-yl)phenyl]acetamide 102N-[4-(5-Methoxy-2-oxo-[1,3,4]oxadiazol-3- 492 491.5yl)phenyl]-3,3,3-triphenylpropionamide 103N-[4-(5-Methoxy-2-oxo-[1,3,4]oxadiazol-3- 448 447.3yl)phenyl]-3,5-bis-trifluoromethylbenzamide 1044-Cyano-N-[4-(5-methoxy-2-oxo-[1,3,4] 337 336.3oxadiazol-3-yl)phenyl]-benzamide 105 Nonanoic acid[4-(5-methoxy-2-oxo-[1,3,4] 348 347.4 oxadiazol-3-yl)phenyl]amide 106Methyl 9-[4-(5-methoxy-2-oxo-[1,3,4] 406 405.4oxadiazol-3-yl)phenyl-carbamoyl]nonanoate 107 Undecanoic acid[4-(5-methoxy-2-oxo-[1,3, 376 375.5 4]oxadiazol-3-yl)phenyl]amide 1084-[4-(5-Methoxy-2-oxo-[1,3,4]oxadiazol-3- 394 393.3yl)phenylcarbamoyl]-benzenesulfonyl fluoride 109 11-Phenoxyundecanoicacid [4-(5-methoxy- 468 467.6 2-oxo-[1,3,4]-oxadiazol-3-yl)phenyl]amide110 N-[4-(5-Methoxy-2-oxo-[1,3,4]oxadiazol-3- 416 415.4yl)phenyl]-2,3-diphenylpropionamide 1114-Chloro-N-[4-(5-methoxy-2-oxo-[1,3,4] 360 359.8oxadiazol-3-yl)phenyl]-2-methylbenzamide 1126-Chloro-N-[4-(5-methoxy-2-oxo-[1,3,4] 347 346.7oxadiazol-3-yl)phenyl]nicotinamide 1135-Fluoro-N-[4-(5-methoxy-2-oxo-[1,3,4] 344 343.3oxadiazol-3-yl)phenyl]-2-methylbenzamide 114N-[4-(5-Methoxy-2-oxo-[1,3,4]oxadiazol-3- 354 353.4yl)phenyl]-2,4,6-trimethylbenzamide 115N-[4-(5-Methoxy-2-oxo-[1,3,4]oxadiazol-3- 388 387.4yl)phenyl]-3-naphthalen-2-ylacrylamide 116 5-Oxo-5-phenylpentanoic acid[4-(5- 382 381.4 methoxy-2-oxo-[1,3,4]-oxadiazol-3-yl) phenyl]amide 1173-(2,4-Dichlorobenzylsulfanyl)thiophene-2- 509 508.4 carboxylic acid[4-(5-methoxy-2-oxo-[1,3,4] oxadiazol-3-yl)phenyl]amide 1182-Fluoro-N-[4-(5-methoxy-2-oxo-[1,3,4] 398 397.3oxadiazol-3-yl)phenyl]-4-trifluoromethyl- benzamide 1191-Hexyl-3-[3-(5-methoxy-2-oxo-[1,3,4] 335 334.4oxadiazol-3-yl)phenyl]urea 120 1-(4-Bromophenyl)-3-[3-(5-methoxy-2-oxo-406 405.2 [1,3,4]oxadiazol-3-yl)phenyl]urea 1211-[3-(5-Methoxy-2-oxo-[1,3,4]oxadiazol-3- 357 356.3yl)phenyl]-3-(2-methoxyphenyl)urea 122 Ethyl2-[3-[3-(5-methoxy-2-oxo-[1,3,4]oxa- 427 426.4diazol-3-yl)phenyl]-ureido]-3-phenyl- propionate 1231-(2,6-Diisopropylphenyl)-3-[3-(5-methoxy- 411 410.52-oxo-[1,3,4]oxadiazol-3-yl)phenyl]urea 1241-[3-(5-Methoxy-2-oxo-[1,3,4]oxadiazol-3- 363 362.4yl)phenyl]-3-octylurea 125 1-(4-Fluorobenzyl)-3-[3-(5-methoxy-2-oxo- 359358.3 [1,3,4]oxadiazol-3-yl)phenyl]urea 1261-(2-Ethylphenyl)-3-[3-(5-methoxy-2-oxo- 355 354.4[1,3,4]oxadiazol-3-yl)phenyl]urea 127 Ethyl6-[3-[3-(5-methoxy-2-oxo-[1,3,4] 393 392.4oxadiazol-3-yl)phenyl]-ureido]hexanoate 1281-(2,6-Dimethoxyphenyl)-3-[3-(5-methoxy- 387 386.42-oxo-[1,3,4]oxadiazol-3-yl)phenyl]urea 1295-Methoxy-3-[4-[(thiophen-3-ylmethyl) 304 303.3amino]phenyl]-3H-[1,3,4]oxadiazol-2-one 1304-[[4-(5-Methoxy-2-oxo-[1,3,4]oxadiazol-3- 437 436.3yl)phenylamino]methyl]-benzonitrile tri- fluoroacetate 1313-[4-(2-Bromo-4,5-dimethoxybenzylamino) 437 436.3phenyl]-5-methoxy-3H-[1,3,4]oxadiazol-2- one 1323-[4-(3-Ethoxy-4-methoxybenzylamino) 486 485.4phenyl]-5-methoxy-3H-[1,3,4]oxadiazol- 2-one trifluoroacetate 133 Methyl4-[[4-(5-methoxy-2-oxo-[1,3,4] 470 469.4oxadiazol-3-yl)phenylamino]methyl]benzoate trifluoroacetate 1344-[[4-(5-Methoxy-2-oxo-[1,3,4]oxadiazol-3- 356 355.3yl)phenylamino]-methyl]phenyl acetate 1355-Methoxy-3-[4-(pentafluorophenylmethyl- 388 387.3amino)phenyl]-3H-[1,3,4]oxadiazol-2-one 1363-[4-(4-Benzyloxybenzylamino)phenyl]-5- 518 517.5methoxy-3H-[1,3,4]oxadiazol-2-one trifluoroacetate 1373-[4-(3,3-Dichlorononylamino)phenyl]-5- 517 516.3methoxy-3H-[1,3,4]oxadiazol-2-one trifluoroacetate 1382-[[4-(5-Methoxy-2-oxo-[1,3,4]oxadiazol-3- 323 322.3yl)phenylamino]-methyl]benzonitrile 1393-[4-(Cyclohexylmethylamino)phenyl]-5- 304 303.4methoxy-3H-[1,3,4]oxadiazol-2-one 1405-Methoxy-3-[4-(2,3,5-trichlorobenzyl- 515 514.7amino)phenyl]-3H-[1,3,4]oxadiazol-2-one trifluoroacetate 1413-[4-(5-Bromo-2-fluorobenzylamino) 509 508.2phenyl]-5-methoxy-3H-[1,3,4]oxadiazol-2- one trifiuoroacetate 1423-[4-(4-Hexyloxybenzylamino)phenyl]-5- 512 511.5methoxy-3H-[1,3,4]oxadiazol-2-one trifluoroacetate 1435-Methoxy-3-[4-[3-(3-trifluoromethyl- 572 571.4phenoxy)benzylamino]-phenyl]-3H-[1,3, 4]oxadiazol-2-one trifluoroacetate144 3-[4-[(2-Chloroquinolin-3-ylmethyl)amino] 497 496.8phenyl]-5-methoxy-3H-[1,3,4]oxadiazol-2- one trifluoroacetate 145 Methyl3-methoxy-5-[[4-(5-methoxy-2-oxo- 501 500.4[1,3,4]oxadiazol-3-yl)phenylamino]methyl] pyridine-2-carboxylatetrifluoroacetate 146 4-[[4-(5-Methoxy-2-oxo-[1,3,4]oxadiazol-3- 454453.5 yl)phenylamino]-methyl]phenyl benzenesulfonate 1472-(2,6-Dimethyl-4-methylsulfanylphenoxy)- 416 415.5N-[3-(5-methoxy-2-oxo-[1,3,4]oxadiazol-3- yl)phenyl]acetamide 1481-(2,4-Difluorophenyl)-3-[4-(5-methoxy-2- 363 362.3oxo-[1,3,4]oxadiazol-3-yl)phenyl]urea 1491-[4-(5-Methoxy-2-oxo-[1,3,4]oxadiazol-3- 419 418.4yl)phenyl]-3-(4-phenoxyphenyl)urea 1501-(2,6-Difluorophenyl)-3-[4-(5-methoxy-2- 363 362.3oxo-[1,3,4]oxadiazol-3-yl)phenyl]urea 1511-Butyl-3-[4-(5-methoxy-2-oxo-[1,3,4] 307 306.3oxadiazol-3-yl)phenyl]urea 152 1-(2-Ethoxyphenyl)-3-[4-(5-methoxy-2-oxo-371 370.4 [1,3,4]oxadiazol-3-yl)phenyl]urea 1531-(2,6-Dibromo-4-fluorophenyl)-3-[4-(5- 503 502.1methoxy-2-oxo-[1,3,4]oxadiazol-3-yl) phenyl]urea 1541-(4-Butoxyphenyl)-3-[4-(5-methoxy-2-oxo- 399 398.4[1,3,4]oxadiazol-3-yl)phenyl]urea 1551-[4-(5-Methoxy-2-oxo-[1,3,4]oxadiazol-3- 411 410.3yl)phenyl]-3-(4-trifluoromethoxyphenyl)urea 1561-Benzyl-3-[4-(5-methoxy-2-oxo-[1,3,4] 341 340.3oxadiazol-3-yl)phenyl]urea 157 1-(3-Fluorophenyl)-3-[4-(5-methoxy-2-oxo-345 344.3 [1,3,4]oxadiazol-3-yl)phenyl]urea 158 Ethyl6-[3-[4-(5-methoxy-2-oxo-[1,3,4] 393 392.4oxadiazol-3-yl)phenyl]-ureido]hexanoate 1591-Biphenyl-4-yl-3-[4-(5-methoxy-2-oxo-[1,3, 403 402.44]oxadiazol-3-yl)phenyl]urea 160 Butyl 2-[3-[4-(5-methoxy-2-oxo-[1,3,4]427 426.4 oxadiazol-3-yl)phenyl]-ureido]benzoate 1615-Methoxy-3-[3-(7-methoxy-3,7-dimethyl- 492 491.5octylamino)phenyl]-3H-[1,3,4]oxadiazol-2- one trifluoroacetate 1625-Methoxy-3-[3-[(thiophen-2-ylmethyl) 418 417.4amino]phenyl]-3H-[1,3,4]oxadiazol-2-one trifluoroacetate 1633-(3-Hexylaminophenyl)-5-methoxy-3H-[1, 406 405.4 3,4]oxadiazol-2-onetrifluoroacetate 164 5-Methoxy-3-[3-(3-phenylpropylamino) 440 439.4phenyl]-3H-[1,3,4]oxadiazol-2-one trifluoroacetate 1655-Methoxy-3-(3-undecylaminophenyl)-3H- 476 475.5 [1,3,4]oxadiazol-2-onetrifluoroacetate 166 5-Methoxy-3-[3-[(3-trifluoromethylphenoxy) 572571.4 benzylamino]phenyl]-3H-[1,3,4]oxadiazol-2- one trifluoroacetate167 3-[3-[(2-Chloroquinolin-3-ylmethyl)amino] 497 496.8phenyl]-5-methoxy-3H-[1,3,4]oxadiazol-2- one trifluoroacetate 1684-[[3-(5-Methoxy-2-oxo-[1,3,4]oxadiazol-3- 586 585.5yl)phenylamino]-methyl]phenyl 4-fluoro- benzenesulfonatetrifluoroacetate 169 5-Methoxy-3-[3-(3,4,5-trifluorobenzylamino) 466465.3 phenyl]-3H-[1,3,4]oxadiazol-2-one trifluoroacetate 1703-[3-(3,5-Bistrifluoromethylbenzylamino) 548 547.3phenyl]-5-methoxy-3H-[1,3,4]oxadiazol-2- one trifluoroacetate 1713-(3-Dec-4-enylaminophenyl)-5-methoxy- 460 459.53H-[1,3,4]oxadiazol-2-one trifluoroacetate 1723-[3-(3-Cyclopentyl-2-phenethyloxybenzyl- 600 599.6amino)phenyl]-5-methoxy-3H-[1,3,4] oxadiazol-2-one trifluoroacetate 1734-[[3-(5-Methoxy-2-oxo-[1,3,4]oxadiazol-3- 437 436.3yl)phenylamino]methyl]-benzonitrile trifluoroacetate 1745-Methoxy-3-[3-[(6-methylpyridin-2- 427 426.3ylmethyl)amino]phenyl]-3H-[1,3,4] oxadiazol-2-one trifluoroacetate 1753-[3-(2-Benzyloxyethylamino)phenyl]-5- 456 455.4methoxy-3H-[1,3,4]oxadiazol-2-one trifluoroacetate 1763-[3-(2,6-Difluorobenzylamino)phenyl]-5- 448 447.3methoxy-3H-[1,3,4]oxadiazol-2-one trifluoroacetate M.p. ° C. 177Dodecanoic acid [4-(5-methoxy-2-oxo-[1,3,4]  93oxadiazol-3-yl)phenyl]amide 178 Octadec-9-enoic acid[4-(5-methoxy-2-oxo-[1,3,4]  67 oxadiazol-3-yl)phenyl]-amide 1792-Methoxyethyl [4-(5-methoxy-2-oxo-[1,3,4] 117oxadiazol-3-yl)-2-methylphenyl]carbamate 1801-(4-Hydroxycyclohexyl)-3-[4-(5-methoxy-2-oxo- 220[1,3,4]oxadiazol-3-yl)-2-methylphenyl]urea 1811,1-Dibutyl-3-[4-(5-methoxy-2-oxo-[1,3,4] Oiloxadiazol-3-yl)-2-methyl-phenyl]urea 1825-Methoxybenzofuran-2-carboxylic acid [4-(5- 199methoxy-2-oxo-[1,3,4]oxadiazol-3-yl)-2- methylphenyl]amide 1834-Methylpiperazine-1-carboxylic acid [4-(5- Oilmethoxy-2-oxo-[1,3,4]oxadiazol-3-yl)-2- methylphenyl]amide 1841-Methylpiperidin-4-yl [4-(5-methoxy-2-oxo-[1,3, 2354]oxadiazol-3-yl)-2-methylphenyl]carbamate 185 Cyclohexyl[4-(5-methoxy-2-oxo-[1,3,4] 163oxadiazol-3-yl)-2-methylphenyl]-carbamate 1864-Benzylpiperidine-1-carboxylic acid [4-(5- 146methoxy-2-oxo-[1,3,4]oxadiazol-3-yl)-2-methyl- phenyl]amide 1871-(2-Diisopropylaminoethyl)-3-[4-(5- 136methoxy-2-oxo-[1,3,4]oxadiazol-3-yl)-2- methylphenyl]urea 1884-(2-{3-[4-(5-Methoxy-2-oxo-[1,3,4]oxadiazol-3- 200yl)-2-methylphenyl]-ureido}ethyl)benzenesulfon- amide 1891-(1-Benzylpiperidin-4-yl)-3-[4-(5-methoxy-2- 198oxo-[1,3,4]oxadiazol-3-yl)-2-methylphenyl]urea 1901-(4-Isopropylphenyl)-3-[4-(5-methoxy-2-oxo-[1, 2003,4]oxadiazol-3-yl)-2-methylphenyl]urea 1912-{3-[4-(5-Methoxy-2-oxo-[1,3,4]oxadiazol-3-yl)- 2462-methylphenyl]ureido}-3-methylbutyric acid 1921,2,3,4-Tetrahydronaphth-1-yl [4-(5-methoxy-2- 159oxo-[1,3,4]oxadiazol-3-yl)-2-methylphenyl] carbamate 193 1-Phenylethyl[4-(5-methoxy-2-oxo-{1,3,4] Oiloxadiazol-3-yl)-2-methyl-phenyl]carbamate 194 4-Isopropylbenzyl[4-(5-methoxy-2-oxo-[1,3,4]  88 oxadiazol-3-yl)-2-methylphenyl]carbamate195 4-Trifluoromethoxybenzyl [4-(5-methoxy-2-oxo-  82[1,3,4]oxadiazol-3-yl)-2-methylphenyl]carbamate 196 3,5-Dichlorobenzyl[4-(5-methoxy-2-oxo-[1,3,4] 169 oxadiazol-3-yl)-2-methylphenyl]carbamate197 Biphenyl-2-ylmethyl [4-(5-methoxy-2-oxo-[1,3,4] 138oxadiazol-3-yl)-2-methylphenyl]carbamate 1985-Chlorobenzofuran-2-carboxylic acid-[4-(5- 210methoxy-2-oxo-[1,3,4]oxadiazol-3-yl)-2-methyl- phenyl]amide 1995-Chlorobenzofuran-2-carboxylic acid [4-(5- 209methoxy-2-oxo-[1,3,4]oxadiazol-3-yl)phenyl] amide

We claim:
 1. Compounds of the formula 1

in which: R¹ is C₁-C₆-alkyl, C₃-C₉-cycloalkyl, wherein both groups areoptionally substituted one or more times by phenyl, C₁-C₄-alkyloxy,S—C₁-C₄-alkyl, N(C₁-C₄-alkyl)₂, and wherein phenyl is optionallysubstituted one or more times by halogen, C₁-C₄-alkyl, C₁-C₄-alkyloxy,nitro, CF₃; and R², R³, R⁴ and R⁵ independently of one another arehydrogen, halogen, nitro, C₁-C₄-alkyl, C₁-C₉-alkyloxy;C₆-C₁₀-aryl-C₁-C₄-alkyloxy, C₆-C₁₀-aryloxy, C₆-C₁₀-aryl,C₃-C₈-cycloalkyl or O—C₃-C₈-cycloalkyl, each of which is optionallysubstituted once, twice or three times by halogen, CF₃, C₁-C₄-alkyloxyor C₁-C₄-alkyl; 2-oxopyrrolidin-1-yl, 2,5-dimethylpyrrol-1-yl orNR⁶-A-R⁷, with the proviso that R², R³, R⁴ and R⁵ are not simultaneouslyhydrogen, and at least one of the radicals R², R³, R⁴ or R⁵ is theradical 2-oxopyrrolidin-1-yl, 2,5-dimethylpyrrol-1-yl, or NR⁶-A-R⁷, andwherein: R⁶ is hydrogen, C₁-C₄-alkyl or C₆-C₁₀-aryl-C₁-C₄-alkyl, wherearyl may be substituted by halogen, CF₃, C₁-C₈-alkyloxy or C₁-C₄-alkyl;A is a single bond, CO_(n), SO_(n), or CONH; n is 1 or 2; R⁷ ishydrogen; C₁-C₁₈-alkyl or C₂-C₁₈-alkenyl, wherein C₁-C₁₈-alkyl orC₂-C₁₈-alkenyl are optionally substituted one to three times byC₁-C₄-alkyl, halogen, CF₃, C₁-C₄-alkyloxy, N(C₁-C₄-alkyl)₂, —COOH,C₁-C₄-alkyloxycarbonyl, C₆-C₁₂-aryl, C₆-C₁₂-aryloxy,C₆-C₁₂-arylcarbonyl, C₆-C₁₀-aryl-C₁-C₄-alkyloxy or oxo, wherein aryl isin turn optionally substituted by halogen, C₁-C₄-alkyl, aminosulfonyl ormethylmercapto; C₆-C₁₀-aryl-C₁-C₄-alkyl, C₅-C₈-cycloalkyl-C₁-C₄-alkyl,C₅-C₈-cycloalkyl, C₆-C₁₀-aryl-C₂-C₆-alkenyl, C₆-C₁₀-aryl, biphenylyl,biphenylyl-C₁-C₄-alkyl, indanyl, each of which is optionally substitutedonce or twice by C₁-C₁₈-alkyl, C₁-C₁₈-alkyloxy, C₃-C₈-cycloalkyl, COOH,hydroxyl, C₁-C₄-alkylcarbonyl, C₆-C₁₀-aryl-C₁-C₄-alkyl,C₆-C₁₀-aryl-C₁-C₄-alkyloxy, C₆-C₁₀-aryloxy, nitro, cyano, C₆-C₁₀-aryl,fluorosulfonyl, C₁-C₆-alkyloxycarbonyl, C₆-C₁₀-arylsulfonyloxy, pyridyl,NHSO₂-C₆-C₁₀-aryl, halogen, CF₃ or OCF₃, wherein alkyl is in turnoptionally substituted by C₁-C₄-alkyloxycarbonyl, CF₃ or carboxyl, andaryl is also optionally substituted by halogen, CF₃ or C₁-C₄-alkyloxy;or the group Het-(CH₂)_(r)—, wherein r=0, 1, 2 or 3 and Het=a saturatedor unsaturated 5-7-membered heterocycle, optionally benzo-fused andoptionally substituted by C₁-C₄-alkyl, C₆-C₁₀-aryl, halogen,C₁-C₄-alkyloxy, C₁-C₄-alkyloxycarbonyl, C₆-C₁₀-aryl-C₁-C₄-alkyl,C₆-C₁₀-aryl-C₁-C₄-alkylmercapto or nitro, wherein the benzo-fused arylis in turn optionally substituted by halogen, C₁-C₄-alkyloxy or CF₃ andthe alkyl in arylalkyl is also optionally by methoxy and CF₃, and theirpharmaceutically acceptable salts and acid addition salts.
 2. Compoundsof the formula 1 as claimed in claim 1 , in which R¹ is C₁-C₄-alkyl. 3.Compounds of the formula 1 as claimed in claim 1 , in which R¹ ismethyl.
 4. Compounds of the formula 1 as claimed in claim 1 , in whichR⁵ is hydrogen.
 5. Compounds of the formula 1 as claimed in claim 1 , inwhich R² is hydrogen, halogen, C₁-C₄-alkyl, C₁-C₉-alkyloxy or amino. 6.Compounds of the formula 1 as claimed in claim 1 , in which R³ ishydrogen, C₁-C₄-alkyl, C₆-C₁₀-aryl-C₁-C₄-alkyloxy, which is optionallysubstituted in the aryl moiety by halogen, or is NR⁶-A-R⁷ whereinR⁶=hydrogen or benzyl, A=single bond and R⁷=C₆-C₁₀-aryl-C₁-C₄-alkyl,which is optionally substituted by halogen, CF₃, cyano,phenyl-C₁-C₄-alkyloxy, CF₃-phenoxy, C₅-C₈-cycloalkyl orfluorosulfonyloxy; C₁-Ci₂-alkyl, which is optionally substituted byC₁-C₄-alkyloxy, phenyl, CF₃ or phenyl-C₁-C₄-alkyloxy; C₂-C₁₂-alkenyl orthe group Het-(CH₂)_(r)—, wherein r=0 or 1, and Het=a saturated orunsaturated 5-7-membered heterocycle, which is optionally benzo-fusedand optionally substituted by C₁-C₄-alkyl or halogen.
 7. Compounds ofthe formula 1 as claimed in claim 1 , in which R⁴ is hydrogen,2-oxopyrrolidin-1-yl, 2,5-dimethylpyrrol-1-yl, orC₆-C₁₀-aryl-C₁-C₄-alkyloxy, which is optionally substituted by halogen.8. Compounds of the formula 1 as claimed in claim 1 , in which: R⁴ isNR⁶-A-R⁷, wherein R⁶=hydrogen or methyl, A=single bond and R⁷=hydrogen;C₁-C₁₂-alky, which is optionally substituted once or twice by halogen;C₂-C₁₈-alkenyl, which is optionally substituted once or twice byC₁-C₄-alkyl or C₁-C₄-alkyloxycarbonyl; C₆-C₁₀-aryl-C₁-C₄-alky, which isoptionally substituted by halogen, C₁-C₆-alkyloxy, CF₃, cya no,C₅-C₆-cycloalkyl, C₁-C₄-alkyloxycarbonyl, C₆-C₁₀-aryl-C₁-C₄-alkyl,C₆-C₁₀-aryl-C₁-C₄-alkyloxy, wherein aryl is further optionallysubstituted by halogen or CF₃; C₅-C₈-cycloalkyl-C₁-C₄-alkyl ; or thegroup Het-(CH₂)r—, wherein r=1, 2 or 3 and Het=a saturated orunsaturated 5-7-membered heterocycle, which is optionally substituted byhalogen, C₁-C₄-alkyloxy or C₁-C₄-alkyloxycarbonyl.
 9. Compounds of theformula 1 as claimed in claim 1 , in which: R⁴ is NR⁶-A-R⁷ whereinR⁶=hydrogen, A=—CO— and R⁷ C₁-C₁₈-alkyl, which is optionally substitutedby halogen, phenyl, phenoxy, phenylcarbonyl or C₁-C₄-alkyloxycarbonyl,wherein phenoxy is optionally substituted by methyl, halogen ormethylmercapto; C₂-C₁₈-alkenyl, which is optionally substituted byC₆-C₁₀-aryl; C₆-C₁₀-aryl, which is optionally substituted by halogen,C₁-C₈-alkyl, phenyl-C₁-C₄-alkyl, CF₃, OCF₃, fluorosulfonyl,C₁-C₄-alkyloxycarbonyl, phenoxy, wherein aryl is optionally substitutedby C₁-C₄-alkyloxy; C₆-C₁₀-aryl-C₁-C₄-alkyl, wherein alkyl is optionallysubstituted by methoxy or CF₃ and aryl by halogen; or the groupHet-(CH₂)_(r)—, wherein r=0 and Het=a saturated or unsaturated5-7-membered heterocycle, which is optionally benzo-fused and optionallysubstituted by C₁-C₄-alkyl, halogen, C₁-C₄-alkyloxy, halophenyl orhalobenzylmercapto, wherein benzo-fused aryl is optionally substitutedby halogen or methoxy.
 10. Compounds of the formula 1 as claimed inclaim 1 , in which: R⁴ is NR⁶-A-R⁷, wherein R⁶=hydrogen, A=—CO₂— andR⁷=C₁-C₁₈-alkyl, which is substituted by CF₃ or phenyl; C₆-C₁₀-aryl;C₆-C₁₀-aryl-C₁-C₄-alkyl, which is substituted by C₁-C₄-alkyl, halogen,CF₃ or OCF₃, benzyloxy or phenyl; or the group Het-(CH₂)_(r)—, whereinr=0 or 1 and Het=a saturated or unsaturated 5-7-membered heterocycle,which is optionally benzo-fused and optionally substituted byC₁-C₄-alkyl or benzyl.
 11. Compounds of the formula 1 as claimed inclaim 1 , in which: R⁴ is NR⁶-A-R, wherein R⁶=hydrogen, A=—SO₂— andR⁷=C₁-C₆-alky, which is optionally substituted by CF₃; C₂-C₄-alkenyl,which is optionally substituted by phenyl; C₆-C₁₀-aryl, which isoptionally substituted by C₁-C₆-alkyl, halogen, C₁-C₄-alkyloxy orbenzyl; biphenylyl-C₁-C₄-alkyl substituted by halogen; or the groupHet-(CH₂)_(r)—, wherein r=0 and Het=a saturated or unsaturated5-7-membered heterocycle.
 12. Compounds of the formula 1 as claimed inclaim 1 , in which: R⁴ is NR⁶-A-R⁷, wherein R⁶=hydrogen, A=—CO—NH— andR⁷=C₁-C₁₀-alkyl, which is optionally substituted byC₁-C₄-alkyloxycarbonyl, N(C₁-C₄-alkyl)₂ or phenyl, which is in turnoptionally substituted by halogen or aminosulfonyl; C₆-C₁₀-aryl, whichis optionally substituted by C₁-C₆-alkyl, C₁-C₆-alkyloxy,C₁-C₆-alkyloxycarbonyl, phenoxy, OCF₃, benzyl or pyridyl, wherein alkylis optionally substituted by C₁-C₄-alkyloxycarbonyl or carboxyl;C₅-C₈-cycloalky, which is optionally substituted by hydroxyl, orindanyl; or the group Het-(CH2)r—, wherein r=0 or 1 and Het=a saturatedor unsaturated 5-7-membered heterocycle, which is optionally substitutedby benzyl.
 13. A process for preparing compounds of the formula 1 asclaimed in any one of claims 1 to 12 , comprising the steps of:

reacting hydrazines of the formula 2 with chloroformic esters of theformula 3 or other reactive carbonic ester derivatives in which R¹, R²,R³, R⁴ and R⁵ are as defined in claim 1 to give the compounds of theformula 4, acylating the compounds of the formula 4 with phosgene,carbonyldiimidazole, diphosgene or triphosgene, to give the compounds ofthe formula 5, and cyclizing the compounds of the formula 5 into thecompounds of the formula
 1. 14. A process according to claim 13 furthercomprising the step of reacting said compounds of formula 1 with asuitable agent to form pharmaceutically acceptable salts or acidaddition salts.
 15. A process according to claim 13 , further comprisingthe step of chemical modification of the radicals R₂-R₅ by reduction ofnitro to amino radicals, acylation or alkylation.
 16. A processaccording to claim 15 further comprising the step of reacting saidcompounds of formula 1 with a suitable agent to form pharmaceuticallyacceptable salts or acid addition salts.
 17. Compounds of the formula 1as claimed in any one of claims 1 to 12 for use in a pharmaceuticalcomposition having an inhibitory effect on hormone-sensitive lipase,HSL.
 18. Compounds of the formula 1 as claimed in any one of claims 1 to12 for use in a pharmaceutical composition useful for treatingnon-insulin-dependent diabetes mellitus or diabetic syndrome.
 19. Apharmaceutical composition for treating non-insulin-dependent diabetesmellitus or diabetic syndrome, comprising at least one of the compoundsof formula 1 as claimed in any one of claims 1 to 12 .